Preparation of 2-substituted-6-pyridyl-nicotinic acids

ABSTRACT

Intermediate 2-R1NH-6-Q&#39;&#39;&#39;&#39;&#39;&#39;-nicotinic acid (V&#39;&#39;), where R1 is lower-alkyl and Q&#39;&#39;&#39;&#39;&#39;&#39; is 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents, is prepared in the three steps of: hydrolyzing 1,2-dihydro-2-oxo-6-Q&#39;&#39;&#39;&#39;&#39;&#39;-nicotinonitrile (VII) to produce 1,2-dihydro-2-oxo-6-Q&#39;&#39;&#39;&#39;&#39;&#39;-nicotinic acid (VIII); halogenating VIII to produce 2-halo-6-Q&#39;&#39;&#39;&#39;&#39;&#39;-nicotinic acid (VI&#39;&#39;); and, reacting VI&#39;&#39; with R1NH2 to produce V&#39;&#39;. Also shown are the steps of: reacting 2-halo-6-Q&#39;&#39;&#39;&#39;-nicotinic acid (VI), where Q&#39;&#39;&#39;&#39; is as Q&#39;&#39;&#39;&#39;&#39;&#39; and also lower-alkyl, to produce 2-R1NH-6-Q&#39;&#39;&#39;&#39;-nicotinic acid (V); heating V with a lower-alkyl chloroformate or phosgene to produce 1-R1-7-Q&#39;&#39;&#39;&#39;-1H,4H-pyrido(2,3-d)(1,3)oxazine-2,4-dione (I&#39;&#39;); converting I&#39;&#39; where Q&#39;&#39;&#39;&#39; is CH3 to its 8-oxide and reacting the 8-oxide with a lower-alkanoic acid anhydride to produce I where 7-CH3 is converted to 7-(lower-alkanoyloxymethyl); reacting 1-R1-7-Q-1H,4H-pyrido(2,3-d)(1,3)oxazine-2,4-dione, where Q is as Q&#39;&#39;&#39;&#39; and also lower-alkanoyloxymethyl, with R2-C( O)CH2COOR, where R2 is H or CH3 and R is lower-alkyl, to produce lower-alkyl 1-R11,4-dihydro-2-R2-4-oxo-7-Q-1,8-naphthyridine-3-carboxylate (III); and, hydrolyzing III to obtain 1-R1-1,4-dihydro-2-R2-4-oxo-7-Q&#39;&#39;1,8-naphthyridine-3-carboxylic acid (IV), where Q&#39;&#39; is like Q but having hydroxymethyl in place of lower-alkanoyloxymethyl.

United States Patent [191 Brundage et al.

[ PREPARATION 'OF 2-SUBSTITUTED-6-PYRIDYL-NICOTINIC ACIDS [75]Inventors: Ruth Pauline Brundage; George Y.

Lesher, both of Schodack, NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: Mar. 20, 1974 [21] Appl. No.: 452,806

Related US. Application Data [62] Division of Ser. No. 346,190, March29, 1973, Pat.

Klingsber, Pyridine and Derivatives, Part 3,

(1962), PP. 197, 245. Bergstrom, Chem. Reviews, Vol. 35, No. 2, (1944),pp. 137.

Primary Examiner-I-Ienry R. Jiles Assistant ExaminerRobert W. RamsuerAttorney, Agent, or Firm-Robert K. Bair; B. Woodrow Wyatt Dec. 23, 1975[57] ABSTRACT Intermediate 2-R NH-6-Q"'-nicotinic acid (V), where R, islower-alkyl and Q is 4(or 3)-pyridyl or 4(or 3)-pyridyl having one ortwo lower-alkyl substituents, is prepared in the three steps of:hydrolyzing l,2- dihydro-2-oxo-6-Q"'-nicotinonitrile (VII) to producel,2-dihydro-2'oxo-6-Q-nicotinic acid (VIII); halogenating VIII toproduce 2-halo-6-Q"'-nicotinic acid (VI); and, reacting VI with R NH toproduce V. Also shown are the steps of: reacting 2-halo-6-Q- nicotinicacid (VI), where Q is as Q' and also lower-alkyl, to produce 2-RNI-I-6-Q"-nicotinic acid (V); heating V with a lower-alkyl chloroformateor phosgene to produce 1-R -7-Q"-lI-I,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione (I'); converting I where Q" is CH, to its8-oxide and reacting the 8-oxide with a lower-alkanoic acid anhydride toproduce I where 7-CI-I is converted to 7-(lower-alkanoyloxymethyl);reacting l-R -7-Q- 1 H,4H-pyrido[2,3-d][ 1,3]oxazine- 2,4-dione, where Qis as Q" and also loweralkanoyloxymethyl, with R -C(=O)CH COOR, where Ris H or CH, and R is lower-alkyl, to produce loweralkyl l-R -1,4-dihydro-2-R -4-ox0-7-Q-1 ,8- naphthyridine-3-carboxylate (III); and,hydrolyzing III to obtain l-R -l ,4-dihydro-2-R -4-oxo-7-Q- l ,8-naphthyridine-3-carboxylic acid (IV), where Q is like Q but havinghydroxymethyl in place of loweralkanoyloxymethyl.

1 Claim, No Drawings PREPARATION OF Z-SUBSTlTUTED-6-PYRIDYL-NICQTINICACIDS l ,1 I Q -N N =0 with a compound of formula II 3 where Q islower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two loweralkyl substituents, R and R are eachlower-alkyl and R is H or CH to produce lower-alkyl 1-R-l,4-dihydrowhere Q,R,R and R are defined as above for formulas l andII, and hydrolyzing III to obtain the corresponding 3-carboxylic acid offormula IV COOH where Q is lower-alkyl, hydroxymethyl, 4(or 3)-pyridylor 4(or 3)-pyridyl having one or two lower-alkyl substituents, I1, islower-alkyl and R is H or CH The compounds of formula IV are disclosedand claimed in US. Pat. No. 3,590,036, issued June 29, 1971. Perhapsbest known because of their high antibacterial activity are nalidixicacid (IV where Q is CH R is C H and R is H) and hydroxynalidixic acid(IV where Q is HOCH R is C H and R is H).

Other aspects of the invention disclosed and claimed in copendingapplication Ser. No. 346,191, now US. Pat. No. 3,838,120, issued Sept.24, 1974, reside in the intermediate l-(lower-alkyl )-7-Q- 1H,4H-pyrido-[2,3- d][l,3]oxazine-2,4-dione of formula I; in the processfor its preparation where Q is Q or as defined for formula I butexcluding lower-alkanoyloxymethyl which comprises heating 2-RNH-6-Q"nicotinic acid of formula V with a .lower-alkyl chloroformate orphosgene, where R is defined as in formula I and Q" is lower-alkyl, 4(or3)-pyridyl or 4(or 3)-pyridyl having one or two loweralkyl substituents,which, in turn, are prepared by reacting the corresponding2halo-6-Q"-nicotinic acid (VI) with a lower-akylamine of the formula RNH and in the process for the preparation of I where Q isloweralkanoyloxymethyl which comprises reacting l-R -7-methyl-1H,4H-pyrido[2,3-d][ l ,3]oxazine-2,3-dione (I where Q is methyl)with an oxidizing agent capable of converting pyridines topyridine-N-oxides to produce 1-R -7-methyl-1H,4H-pyrido[2,3-d][ 1,3]oxazine-2,4- dione-8-oxide and then reacting said 8-oxide with alower-alkanoic acid anhydride to produce I where Q islower-alkanoyloxymethyl.

Aspects of the instant invention reside in the intermediate 2-RNH-6-Q"'-nicotinic acid of formula V COOH where R is lower-alkyl and Q'is 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkylsubstituents, and in the process of its preparation which comprises thecombination of the three steps of hydrolyzing1,2-dihydro-2-oxo-6-Q"-nicotinonitrile (Vll) to producel,2-dihydro-2-oxo-6-Q'"-nicotinic acid (Vlll), halogenating VIII toproduce 2-halo-6-Q"-nicotinic acid (VI') and reacting V1 with alower-alkylamine of the formula R NH to produce V. In addition to saidcombination of the three steps, other process aspects of the inventionare each individual step and the two combinations of two consecutivesteps.

Additional composition aspects of the instant invention reside in thecompounds: 1,2-dihydro-2-oxo-6- Q"-nicotinic acid and its tautomeric2-hydroxy-6-Q")t -nicotinic acid of the respective formulas VIII andVIIIA and, also, 2-halo-6-Q"-nicotinic acid of the formula VI' coonwhere Q" has the meaning designated hereinabove for formula V and X ishalo, preferably chloro or bromo.

Because of the ready availability and/or low cost of intermediatesand/or because of high antibacterial activity of the final products (IIIor IV), preferred process and composition embodiments of the variousaspects of the inventions herein disclosed are those where R is ethyl, Ris hydrogen, halo is chloro, Q is methyl, acetoxymethyl, 4(or3)-pyridyl, 2-methyl-4-pyridyl or 2,6- dimethyl-4-pyridyl, Q is as Q andalso hydroxymethyl, Q" is as Q but excluding acetoxymethyL-and Q'" is4(or 3)-pyridyl, 2-methyl-4-pyridyl or 2,6-dimethyl-4- pyridyl.

The term lower-alkyl, as used herein, e.g., as represented by R, informula I, III or IV or as a substituent of 4(or 3 )-pyridyl whenrepresented by Q in formulas I or III or by Q in formula IV, means alkylradicals having from 1 to 6 carbon atoms which can be arranged asstraight or branched chains, illustrated by methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, n-amyl, n-hexyl, and the like.

The term lower-alkanoyl, as used herein, e.g., in the definition of theQ substituent as lower-alkanoyloxymethyl in formulas l or III, meansalkanoyl radicals having from one to six carbon atoms, including thestraightand branched-chain radicals, illustrated by formyl, acetyl,propionyl (propanoyl), butyryl (butanoyl), isobutyryl(Z-methylpropanoyl) and caproyl (hexanoyl).

Illustrative of the Q substituent in formulas I or III or of the Qsubstituent in formula IV or of the Q" substituent in formula V or ofthe Q'" substituent in formulas V', VI, VII, VIII or VIIIA where Q or Qor Q" or respectively, is 4(or 3)-pyridyl having one or two lower-alkylsubstituents are the following: 2-methyl-4-pyridyl,2,6-dimethyl-4-pyridyl, 3-methyl-4-pyridyl, 2- methyl-3-pyridyl,6-methyl-3-pyridyl (preferably named 2-methyl-5-pyridyl),2,3-dimethyl-4-pyridyl, 2,5-dimethyl-4-pyridyl, 2-ethyl-4-pyridyl,2-isopropyl- 4-pyridyl, 2-n-butyl-4-pyridyl, 2-n-hexyl-4-pyridyl, 2,6-diethyl-4-pyridyl, 2,6-diethyl3-pyridyl, 2,6-diisopropyl-4-pyridyl,2,6-di-n-hexyl-4-pyridyl, and the like.

As shown above, l,2-dihydro-2-oxo-6-Q"-nicotinic acid of formula VIII istautomeric with 2-hydroxy-6- Q"-nicotinic acid of formula VIIIA As withall tautomeric systems, the rate of the transformation VIII VIIIA andthe ratio VIII/VIIIA are dependent on the 4 thermodynamic environment,including the state of aggregation; so that measurements by anyparticular techniques do not necessarily have validity except under theconditions of the measurement, thereby, among other consequences, givingrise to problems for any simple designation of the physical embodiments.

Thus, measurements of the infrared spectra, in potassium bromideadmixture, or in chloroform or mineral oil, indicate existencepredominantly as VIII and the names of the compounds herein thereforeare preferably based on structure VIII, although it is understood thateither or both structures are comprehended.

The intermediate 2-(lower-alkylamino)-6-(loweralkyl)-nicotinic acid (Vwhere Q" is lower-alkyl) is prepared by halogenating the generally known1,2- dihydro-2-oxo-6-(lower-alkyl)nicotinic acid with a halogenatingagent, preferably a chlorinating agent, e.g., PCI PCI POCI SO Cl and thelike, to produce 2-halo-6-(lower-alkyl)-nicotinic acid and then reactingsaid 2-halo acid with a lower-alkylamine (R Nl-l The generally knownintermediate 1,2-dihydro-2- oxo-6-Q"-nicotinonitrile (VII) or tautomer(VIIA) is prepared by the known procedure of first reacting 4(or3)-acetylpyridine or 4(or 3)-acetylpyridine substituted on the pyridinering by one or two lower-alkyl substituents, as represented by Q"-COCI-Iwith ethyl formate and sodium methoxide to yield the sodium salt of Q"'-COCH CHO, e.g., the sodium salt of isonicotinoylacetaldehyde where Q" is4-pyridyl, and then reacting said sodium salt with cyanoacetamide inaqueous medium to produce said 1,2-dihydro-2-oxo-6-Q"'- nicotinonitrile,e.g., where Q'" is 4-pyridyl, also named l,6-dihydro-6-oxo[2,4-bipyridine]-5-carbonitrile.

The molecular structures of said intermediate aspects (I, V-', VI, VIIIand VIIIA) of the inventions herein disclosed and of the final products(III and IV) are assigned on the basis of evidence provided by infrared,ultraviolet and nuclear magnetic resonance spectra, and by thecorrespondence of calculated and found values for the elementaryanalysis for representative examples.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows:

The hydrolysis of nicotinonitrile (VII) or its tautomer (VIIA) toproduce the corresponding 1,2-dihydro-2-oxo-6-Q"'-nicotinic acid ispreferably carried out by refluxing VII (or VIIA) in an aqueous acidicmedium, preferably using from about 1:2 to 1:] parts by volume ofconcentrated (-97%) sulfuric acid and water, respectively. Other aqueousacidic media can be used, e.g., 6N hydrochloric acid, and the like.

The reaction of l,2-dihydro-2-oxo-6-(lower-alkyl)- nicotinic acid (VIII)or 2-hydroxy-6-Q"'-nicotinic acid (VIIIA) with a halogenating agent,preferably a mixture of phosphorus oxychloride and phosphoruspentachloride, is carried out by heating the reactants, preferably atabout 50l 10C. The reaction is conveniently run by refluxing thereactants in chloroform; however, the reaction can be run in the absenceof a solvent or using another inert solvent, e.g., benzene, toluene,xylene, chlorobenzene, methylene dichloride, and the like. Also, otherchlorinating agents can be used, e.g., phosphorus oxychloride orphosphorus pentachloride alone, phosphorus trichloride, thionylchloride, phosgene, phenylphosphonic dichloride, and the like.

The reaction of 2-halo6-Q"(or Q"')-nicotinic acid (VI or VI) with alower-alkylamine, R -NH to produce 2-R NH-6-Q(or Q")-nicotinic acid (Vor V) is conveniently carried out by heating the reactants together in astainless steel autoclave. The reaction temperature is about 75150C.,preferably about 90l10C. Alternatively, a suitable inert solvent can beused, e.g., ethanol, toluene, xylene, benzene, and the like.

The reaction of 2-R NH-6-Q-nicotinic acid (V) with a lower-alkylchloroformate to produce l-R -7-Q"-lH,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione is carried out by heatingthe reactants at about 125175C., preferably about 135-150C. in theabsence or presence of an inert solvent, e.g., xylene. Alternatively,phosgene can be used in place of the lower-alkyl chloroformate.

The reaction of 1-R -7-methyl-1H,4H-pyrido[2,3-d]- [l,3]oxazine-2,3dione(I where Q is methyl) with an oxidizing agent to producel-R,-7-methyl-1H,4H- pyrido[2,3-d][1,3]oxazine-2,4-dione-8-oxide iscarried out by reacting I where Q is methyl with an oxidizing agentcapable of converting pyridines to pyridine-N- oxides, preferably with aper acid, e.g., peracetic acid, perbenzoic acid, 3-chloroperbenzoicacid, and the like,

'orwith other oxidizing agents, e.g., hydrogen peroxide,

in the presence of a suitable solvent inert under the reactionconditions, e.g., acetic acid, chloroform, and the like. The reaction isconveniently run by mixing the reactants carefully at room temperature(about 2025C.) up to about 4050C., preferably with stirring, and thenheating the reaction mixture on a steam bath to ensure completion of thereaction.

The conversion of l-R -7-methyl-lH,4H-pyrido[2,3-]-[1,3]oxazine-2,3-dione-8-oxide to 1-R-7-(loweralkanoyloxymethyl)-1H,4I-I-pyrido[2,3-d][1,3]oxa zine-2,3-dioneis carried out by reacting said 8-oxide with a lower-alkanoic acidanhydride. The reaction is conveniently run using as solvent an excessof the anhydride or the corresponding alkanoic acid, e.g., acetic acidwith acetic anhydride, or any suitable solvent unreactive to saidanhydrides, e.g., acetonitrile, benzene, toluene, dimethylformamide, andthe like. The reaction is generally carried out in the range of about70150C., preferably on a steam bath.

The reaction of 1-R -7-Q-1H,4H-pyrido[2,3-d][1,3]- oxazine-2,4-dione (I)with a lower-alkyl acetoacetate (II, R =CH or formylacetate (II, R =H),the latter preferably as its alkali metal enolate, to produce alower-alkyl l-R -l ,4-dihydro-4-oxo-2-R -7-Q-l ,8-naphthyridine-3-carboxylate (Ill) is carried out by heating thereactants in the range of about 50150C., preferably about 80-120C.,preferably using an inert solvent, e.g., dimethylformamide.Alternatively, the lower-alkyl formylacetate can be prepared in situfrom a lower-alkyl ether or lower-alkanoate (1-6 carbon atoms) of itsenol form, preferably its methyl or ethyl ether or its acetate.

The hydrolysis of lower-alkyl l-R -l,4-dihydro-4- oxo-2-R-7-Q-1,8-naphthyridine-3-carboxylate (III) to produce 1-R-1,4-dihydro-4-oxo-2-R -7-Q-1,8-naphthyridine-3-carboxylic acid (IV) isrun either under acidic or alkaline conditions. The hydrolysis can becarried out from about room temperature (25C.) to about 100C. using,where necessary, an appropriate solvent, e.g., water, ethanol, methanol,acetone, and the like. Various acidic or alkaline solutions can be used,e.g., aqueous hydrochloric acid, hydrobromic acid, sulfuric acid, sodiumhydroxide, potassium hydroxide, calcium hydroxide, and the like.

The best mode contemplated for carrying out the invention is now setforth as follows:

EXAMPLE I 2-Chloro-6-methylnicotinic acid To a mixture of ml. ofphosphorus oxychloride, 340 g. of finely ground phosphorus pentachlorideand 800 ml. of chloroform was added 123 g. of well ground powdered1,Z-dihydro-6-methyl-2-oxonicotinic acid whereupon a slightly exothermicreaction ensued. This reaction mixture was heated to boiling over aperiod of 1 hour and then was refluxed for 8% hours. The reactionmixture was next concentrated in vacuo and then concentrated in vacuo at0.5 mm. after diluting it with methylene dichloride. The resultingresidual brown oil containing some solid was poured into 800 ml. of icewater and the resulting mixture stirred at room temperature for 3 hours.A brown granular precipitate was filtered off and washed with three 60ml. portions of water. The combined aqueous filtrate and washings wereextracted with two 500 ml; portions of chloroform. Said brown granularprecipitate was extracted with the same chloroform and then extractedwith a third 500 ml. portion of boiling chloroform. The combinedchloroform extracts were washed with water, dried over anhydrousmagnesium sulfate, treated with decolorizing charcoal, filtered andconcentrated in vacuo to remove the solvent. The crystalline residue wasrecrystallized from ethyl acetate and dried in vacuo at 60C. for 2 hoursto yield a first crop of 44 g., m.p. l42-149C. and a second crop of 20g., m.p. l38143C. Recrystallization of these two crops plus 7 g. ofproduct obtained by another run from 300 ml. of ethylacetate gave 41.4g. of 2-chloro-6-methylnicotinic acid, m.p. l50151C. Also obtained was asecond crop of 9.3 g., m.p. 141147C. Using molar equivalent quantitiesof phosphorus oxybromide and phosphorus pentabromide in place ofphosphorus oxychloride and phosphorus pentachloride, respectively, 2-bromo-o-methylnicotinic acid is obtained.

EXAMPLE 2 2-Ethylamino-6-methylnicotinic acid A mixture of 41.4 g. of2-chloro-6-methylnicotinic acid and 520 ml. of 70% aqueous ethylaminewas heated in a stainless steel autoclave for 20 hours at C., themaximum pressure being about 200 lbs. per square inch. The reactionmixture was concentrated in vacuo. To the remaining brown oil was added20.3 g. of sodium bicarbonate in 270 m1. of water and the mixture wasconcentrated in vacuo. The resulting residue was taken up in benzene andthe solution concentrated in vacuo to remove the benzene; this benzenetreatment was repeated twice. The residue was dissolved in hot benzene,the solution filtered, and the filtrate concentrated to yield 49 g. ofcrude product, 2-ethylamino-6- methylnicotinic acid, which wasused inExample 3 without further purification. In another run, the crudeproduct (from 10.89 of 2-chloro-6-methylnicotinic acid) wasrecrystallized once from benzene to yield the product as a tan-yellowsolid (9.8 g-), m.p. 1l21l5C. A sample for analysis, m.p. 1 l6-l 18C.,was obtained by recrystallization from benzene-cyclohexane aftertreating the hot benzene solution with decolorizing charcoal andfiltering off the charcoal.

EXAMPLE 3 l-Ethyl-7-methyl-l H,4l-l-pyrido[ 2,3-d][ l ,3 ]-oxazine-2,4-dione To a solution containing 49 g. of 2-ethylamino-6-methylnicotinic acid dissolved in 250 ml. of xylene, was added 400 ml.of ethyl chloroformate and the mixture was refluxed for hours. Thereaction mixture was concentrated in vacuo, the residue taken up inbenzene and the benzene removed in vacuo. The benzene treatment wasrepeated. The residue was crystallized from benzene-cyclohexane to yield29 g. of crystalline product, which had a faint odor of ethylchloroformate. The product was triturated twice with etherzcyclohexane(1:1), the mixture filtered and the product dried in vacuo for two hoursto yield 28.7 g. ofl-ethyl-7-methyl-lH,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione, m.p. l l6l17C.

Alternatively, the above preparation can be carried out using phosgenein place of ethyl chloroformate.

EXAMPLE 4 l-Ethyl-l ,4-dihydro-2,7-dimethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid To a cooled and stirred mixturecontaining 70 ml. of dry dimethylformamide and 4.4 g. of sodium hydride(60%) under an atmosphere of nitrogen was added with stirring 14 ml. ofethyl acetoacetate. After the foaming had subsided (about minutes), tothe stirred mixture was added 22.7 g. ofl-ethyl-7-methylll-l,4H-pyrido[2,3-d][ l ,3 ]oxazine-2,4-dione and theresulting stirred reaction mixture was slowly warmed up to 90C. (on asteam bath) and kept there for 6 hours. The reaction mixture was thenconcentrated in vacuo to yield 37 g. of brown gummy residue containingethyl l-ethyl-l,4-dihydro-2,7-dimethyl-4-oxo-l,8-naphthyridine-3-carboxylate. The residue was dissolved in 250 ml. of 95%ethanol; 36.8 ml. of aqueous sodium hydroxide solution was added; and,the mixture was refluxed with stirring for 2 hours. The hot reactionmixture was filtered and the filtrate concentrated in vacuo. Theresidual solid was dissolved in 280 ml. of water, the solution filteredand the filtrate acidified with acetic acid plus some hydrochloric acidto a pH of 5. The acidic solution was cooled and the separated productwas collected to yield 16.35 g. of tan-white crystals after drying invacuo at 90C. The crystals were recrystallized once fromtetrahydrofuranbenzene and then twice from tetrahydrofuran to yield, aswhite crystals, 7.2 g. of l-ethyl-l,4-dihydro-2,7- dimethyl-4-oxo-l,8-naphthyridine-3-carboxylic acid, m.p. 226227C.

EXAMPLE 5 l-Ethyl-l ,4-dihydro-7-methyl-4-oxo-l,S-naphthyridine-3-carboxylic acid is prepared following the proceduredescribed in Example 4 but using in place of ethyl acetoacetate anequivalent molar quantity of ethyl formylacetate.

EXAMPLE 6 l,2-Dihydro-2-oxo-6-(4-pyridyl)nicotinic Acid To a solutioncontaining 70 ml. of 97% sulfuric acid and 70 ml. of water was added19.7 g. of 1,2-dihydro-2- oxo-6-(4-pyridyl)nicotinonitrile. Theresulting solution was refluxed for 96 hours, allowed to cool and pouredinto 1,500 ml. of water. The solution was neutralized with 35% aqueoussodium hydroxide solution. The resulting precipitate was collected,dried, recrystallized from dimethylformamide (about 1,500 ml.), washedwith ethanol and dried in vacuo at 60C. to yield 5.45 g. ofl,2-dihydro-2-oxo-6-(4-pyridyl)nicotinic acid,

m.p. 300C. with decomposition. A small sample for analysis wasrecrystallized a second time from dimethylformamide.

Following the procedure described in Example 6 but using in place ofl,2-dihydro-2-oxo-6-(4-pyridyl)- nicotinonitrile a molar equivalentquantity of the appropriate l,2-dihydro-2-oxo-6-Q-nicotinonitrile, thereare obtained the corresponding 1,2-dihydro-2- oxo-6-Q'-nicotinic acidsof Examples 7-13:

EXAMPLE 7 l,2-Dihydro-2-oxo-6-(3-pyridyl)nicotinic acid usingl,2-dihydro-2-oxo-6-(3-pyridyl)nicotinonitrile, the latter prepared byreacting the sodium salt of nicotinoylacetaldehyde with cyanoacetamide.

EXAMPLE 1 l 6-( 3-Ethyl-4-pyridyl)-l ,2-dihydro-2-oxonicotinic acidusing 6-(3-ethyl-4-pyridyl)l ,2-dihydro-2- oxonicotinonitrile, thelatter prepared by reacting the sodium salt of3-ethylisonicotinoylacetaldehyde with cyanoacetamide.

EXAMPLE l2 l,2-Dihydro-6-(2,6-dimethyl-4-pyridyl)-2-oxonicotinic acidusing l,2-dihydro-6-(2,6-dimethyl-4- pyridyl)-2-oxonicotinonitrile, thelatter prepared by reacting the sodium salt of2,6-dimethylisonicotinoylacetaldehyde with cyanoacetamide.

EXAMPLE l3 1,2-Dihydro-6-(3 ,5-dimethyl-4-pyridyl)-2-oxonicotinic acidusing l,2-dihydro-6-(3,5-dimethyl-4- pyridyl)-2-oxonicotinonitrile, thelatter prepared by reacting the sodium salt of3,5-dimethylisonicotinoylacetaldehyde with cyanoacetamide.

Following the procedure described in Example 1 but using in place of1,2-dihydr0-6-methyl-2-oxonicotinic acid a molar equivalent quantity ofthe appropriate l,2-dihydro-2-oxo-6-Q'"-nicotinic acid, there areobtained the following 2-chloro-6-Q'"-nicotinic acids of Examples 14-21:

EXAMPLE 14 2-Chloro-6-(3-pyridyl)nicotinic acid using1,2-dihydro-2-ox0-6-(3-pyridyl)nicotinic acid.

EXAMPLE l5 2-Chloro-6-(2-methyl-4-pyridyl)-nicotinic acid using 1,2-dihydro-6-(2-methyl-4-pyridyl )-2-oxonicotinic acid.

EXAMPLE l6 7 2-Chloro-6-(3-methyl-4-pyridyl)-nicotinic acid using 1,2-dihydro-6-( 3-methyl-4-pyridyl)-2'oxonicotinic acid.

EXAMPLE '1 7 2-Chloro-6-(2-ethyl-4-pyridyl)nicotinic acid using6-(2-ethyl-4-pyridyl)-l ,Z-dihydro-2-oxonicotinic acid.

EXAMPLE 18 2-Chloro-6-(3-ethyl-4-pyridyl)nicotinic acid using6-(3-ethyl-4-pyridyl)-l ,2-dihydro-2-oxonicotinic acid.

EXAMPLE l9 2-Chloro-6-(2,6-dimethyl-4-pyridyl)-nicotinic acid using 1,2-dihydro-6-(2,6-dimethyl-4-pyridyl)-2- oxonicotinic acid.

EXAMPLE 20 2-Chloro-6-(4-pyridyl)nicorinic acid usingl,2-dihydro-2-oXo-6-(4-pyridyl)nicotinic acid.

EXAMPLE 2l 2-Chl0r0-6-(3,5-dimethyl-4-pyridyl)-nicotinic acid usingl,2-dihydro-6-( 3 ,5-dimethyl-4-pyridyl )-2- oxonicotinic acid.

Following the procedure described in Example 2 but using in place of2-chloro-6-methylnicotinic acid or in place of aqueous ethylamine amolar equivalent quantity of the appropriate 2-halo-6-Q"'-nicotinic acidor aqueous lower-alkylamine, respectively, there are obtained thefollowing 2-(lower-a1kylamino)-6Q"-nicotinic acids of Examples 22-33:

EXAMPLE 2'2 2-Ethylamino-6-(3-pyridyl)nicotinic acid using 2-chloro-6-(3-pyridyl)nicotinic acid and ethylamine.

EXAMPLE 23 2-Ethylamino-6-( 2-methyl-4-pyridyl )-nicotinic using2-chloro-6-(2-methyl-4-pyridyl)-nicotinic and ethylamine.

acid acid EXAMPLE 24 2-Ethylamino-6-(3-methyl-4-pyridyl)-nicotinic using2-chloro-6-(3-methyl-4-pyridyl)-nic0tinic and ethylamine.

acid acid EXAMPLE 25 2-Ethylamino-6-(2-ethyl-4-pyridyl)-nicotinic acidusing 2-chloro-6-(2-ethyl-4-pyridyl)nicotinic acid and ethylamine.

EXAMPLE 26 2-Ethylamino-6-(3-ethyl-4-pyridyl)-nicotinic acid using2-chloro-6-(3-ethyl-4-pyridyl)nicotinic acid and ethylamine.

EXAMPLE 27 2-Ethylamino-.6-(2,6-dimethyl-4-pyridyl)-nicotinic acid using2-chloro-6-(2,6-dimethyl-4-pyridyl)-nicotinic acid and ethylamine.

EXAMPLE 28 2-Ethylamino-6-(4-pyridyl)nicotinic acid using 2-chloro-6-(4-pyridyl)nicotinic acid and ethylamine.

Following the procedure described in Example 3 but using in place of2-ethylamino-6-methylnicotinic acid a molar equivalent quantity of theappropriate 2-(lower-alkylarnino)-6-Q"-nicotinic acid, there areobtained the following l-(lower-alkyl)-7-Q-lH,4H

pyrido[2,3-d][ l ,3 ]oxazine-2,4-diones of Examples EXAMPLE 34l-Ethyl-7-(3-pyridyl)-lH,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione using2-ethylamino-6-(3-pyridyl)nicotinic acid.

EXAMPLE 35 l-Ethyl-7-( 2-methyl-4-pyridyl )-l H,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione using 2-ethylamino-6-(2-methyl-4-pyridyl)nicotinic acid.

EXAMPLE 36 I -Ethyl-7-( 3-methyl-4-pyridyl)-l H ,4H-pyrido[2,3- d][ l ,3]oxazine-2,4-dione using 2-ethylamino-6-( 3- methyl-4-pyridyl)nicotinicacid.

EXAMPLE 37 1-Ethyl-7-(2-ethyl-4-pyridyl)- l H,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione using 2-ethylamino-6-(2-ethyl-4-pyridyl)nicotinic acid.

EXAMPLE 38 1-Ethyl-7-( 3-ethyl-4-pyridyl)-l l-l,4H-pyrido[2,3- d][ 1,3]oxazine-2,4-dione using 2-ethylamino-6-(3- ethyl-4-pyridyl)nicotinicacid.

EXAMPLE 39 1-Ethyl-7-(2,6-dimethyl-4-pyridyl)-lHAH- pyrid0[2,3-d] l ,3]oxazine-2,4-dione using ethylamino-6-(2,6-dimethyl-4-pyridyl)nicotinicacid.

EXAMPLE 43 l-n-Butyl-7-(4-pyridyl )-l H,4H-pyrido[2,3-

d][l,3]oxazine-2,4-dione using 2-n-butylamino 6-(4- pyridyl)nicotinicacid.

EXAMPLE 44 l-n-Hexyl-7-(4-pyridyl)-lH,4H-pyrido[2,3- d][ 1,3]oxazine-2,4-dione using 2-n-hexylamino-7-(4- pyridyl)nicotinic acid.

EXAMPLE 451-Ethyl-7-(4-pyridyl)-1H,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione using2-ethylamino-6-(4-pyridyl)nicotinic acid.

Following the procedure described in Example 4 but using in place ofl-ethyl-7-methyl-lH,4H-pyrido[2,3- d]-[l,3]oxazine-2,4-dione a molarequivalent quanty of the appropriate l'(lower-alkyl)-7-Q"'-lH,4H-pyrido[2,3-d][l,3]-oxazine-2,4-dione and either ethyl acetoacetate or anmolar equivalent quantity of ethyl formylacetate, there are obtained the1-(lower-alkyl) l,4-dihydro-2-methyl(or 2-unsubstituted )-4-oxo-7- Q'-l,8-naphthyridine-3-carboxylic acids of Examples 46-57:

EXAMPLE 46 l-Ethyl-l ,4-dihydro-4-0xo-7-( 3-pyridyl)-l,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(3-pyridyl)-lH,4H-pyrido[2,3-d][ l,3]oxazine-2,4-dione and ethyl formylacetate.

EXAMPLE 47 l-Ethyl-l ,4-dihydro-7-(2-methyl-4-pyridyl)-4-oxol,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(2-methyl-4-pyridyl)- l H,4H-pyrido[2,3-d][ l ,3 ]-oxazine- 2,4-dione andethyl formylacetate.

EXAMPLE 48 l -Ethyl-1 ,4-dihydro-2-methyl-7-( 3-methyl-4- pyridyl)-4-0X0-l ,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(3-methyl-4-pyridyl l H,4H-pyrido- [2,3-d][l,3]oxazine-2,4-dione andethyl acetoacetate.

EXAMPLE 49 l-Ethyl-7-(2-ethyl-4-pyridyl)-1,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylic acid using l-Ethyl-7-(2- 12ethyl-4-pyridyl)-l l-l,4H-pyrido[2,3-d][ l ,3 ]oxazine- 2,4-dione andethyl formylacetate.

EXAMPLE 50 1-Ethyl-7-( 3-ethyl-4-pyridyl)-l ,4-dihydro-2-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid usingethyl-7-(3-ethyl-4-pyridyl)-1H,4H-pyrido[2,3-d][ 1,3]-oxazine-2,4-dione-and ethyl acetoacetate.

EXAMPLE 51 1-Ethyl-l,4-dihydro-7-(2,6 -dirnethyl-4-pyridyl)-4-oxo-l,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(2,6-dimethyl-4-pyridyl)-lH,4H-pyrido[2,3-d][1,3]-

oxazine-2,4-dione and ethyl formylacetate.

EXAMPLE 52 l-Ethyl-l ,4-dihydro-2-methyl-7-(3,5-dimethyl-4- pyridyl)-4-oxo-l ,8-naphthyridine-3-carboxylic acid using l-ethyl-7-( 3,5-dimethyl-4-pyridyl 1 H,4H- pyrido-[2,3-d][l,3]oxazine-2,4-dione andethyl acetoacetate.

EXAMPLE 53 1,4-Dihydrol -methyl-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using l-methyl-7-(4-pyridyl)-lH,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione and ethylformylacetate.

EXAMPLE 54 1,4-Dihydro-l-isopropyl-7-(2-methyl-4-pyridyl)-4-oxo-l,8-naphthyridine-3-carboxylic acid using l-isopropyl-7-(2-methyl-4-pyridyl l H,4H-pyrid0 2,3- d][ l,3]-oxazine-2,4-dione andethyl formylacetate.

EXAMPLE 55 l-n-Butyl-l ,4-dihydro-2-methyl-4-oxo-7-(4-pyridyl)-1,S-naphthyridine-3-carboxylic acid using 1-n-butyl-7- (4-pyridyl)-lH,4H-pyrido[2,3-d][ 1 ,3 ]oxazine-2,4- dione and ethyl acetoacetate.

EXAMPLE 56 l-n-HexyH ,4-dihydro-2-methyl-4-oxo 7-(4- pyridyl)-l,8-naphthyridine-3-carboxylic acid usingl-nhexyl-7-(4-pyridyl)-lH,4H-pyrido[2,3-d][1,3]oxazine- 2,4-dione andethyl acetoacetate.

EXAMPLE 57 l-Ethyl-l ,4-dihydro-4-oxo-7-(4-pyridyl )-l,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(4-pyridyl)-1H,4H-pyrido[2,3-d][ i ,3 ]oxazine-2,4-dione and ethyl formylacetate.

We claim:

1. The process which comprises refluxing1,2-dihydro-2-oxo-6-Q"'-nicotinonitrile in an aqueous acidic medium toproduce l,2-dihydro-2-oxo-6-Q"-nicotinic acid, heating said2-oxo-nicotinic acid with a halogenating agent at about 50l 10C. toproduce 2-halo-6- Q"'-nicotinic acid and heating said 2-halo compoundwith R Nl-l at about 75-] 50C. to produce 2-R,NH-6- Q"-nicotinic acidwhere R is lower -alkyl and Q is.

4(or 3)-pyridyl or 4(or 3)-pyridyl having 1 or 2 loweralkylsubstituents.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORREC'HQN PATENTNO. 23,928,366

DATED December 23, 1975 INVENTOR(S) Ruth Pauline Brundage and George Y.Lesher It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

Column 2, line 66, "6-Q"A" should read 6-Q" line 67, omit fiigned andSealed this fourth Day of May 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer ('ummissimu'ruj'larr-nrs and Trademarks

1. THE PROCESS WHICH COMPRISES REFLUXING 1,2-DIHYDRO-2OXO-6-Q"''-NICOTINONITRILE IN AN AQUEOUS ACIDIC MEDIUM TO PRODUCE1,2-DIHYDRO-2-OXO-6-Q"''-NICONTINIC ACID, HEATING SAID 2-OXO-NICOTINICACID WITH A HALOGENATING AGENT AT ABOUT 50*-110*C. TO PRODUCE2-HALO-6-Q"''-NICOTINIC ACID AND HEATING SAID 2-HALO COMPOUND WITH R1NH2AT ABOUT 75*-150*C. TO PRODUCE 2-R1NH-6-Q"''-NICOTINIC ACID WHERE R1 ISLOWER-ALKYL AND Q"'' IS 4(OR 3)-PYRIDYL OR 4(OR 3)-PYRIDYL HAVING 1 OR 2LOWER-ALKYL SUBSTITUENTS.